DESCRIPTION: The aetiology of idiopathic PD (IPD) is complex, involving genetic and environmental factors. The risk of IPD is higher among relatives of cases than controls, but only a small number of multigenerational families with IPD exist. In support of an environmental cause, are the observations that MPTP and occupational manganese exposures both induce PD. Iron accumulates in the substantia nigra in IPD and lactoferrin receptors are increased whereas ferritin concentrations are reduced. This imbalance of iron is posited to accelerate free radical formation and lipid peroxidation. In IPD, activity in complex I of the respiratory chain is reduced in the substantia nigra, particularly for subunits encoded in the mitochondrial genome. MPTP inhibits NADH-CoQ reductase (complex I) in mitochondria, whereas manganese inhibits the Citric Acid Cycle enzyme, mitochondrial aconitase (ACO2). Deficits in ATP production in certain critical neuronal populations are posited to indirectly contribute to the pathogenesis of IPD. During the first three years, the applicants found that, in comparison to controls, patients with IPD have lower concentrations of iron storage and transport proteins, indicating a perturbation in systemic iron metabolism. The patients also have increased caloric intake, suggesting a defect in energy metabolism. The applicants have detected a shifted protein band in serum which, by Western blot, contains ACO2. They also found evidence for allelic association of two dinucleotide repeat makers on chromosome 22q13, which includes the ACO2 gene. These observations lead to the hypothesis that IPD may be the result of a mutation, splicing variant or post-translational modification of ACO2 which, in turn, alters mitochondrial function. The current plan is to extend the epidemiologic inquiry by investigating changes in iron metabolism and caloric intake in IPD, over time and at two critical diseases stages, early (untreated) and late. Additionally, a major laboratory effort will be employed, not only to characterize and determine the frequency of altered forms of ACO2 in IPD and controls, but also to identify ACO2 mutations or splice variants if they exist, and to investigate mitochondrial function in relation to altered ACO2.